Ketene acetals synthesis

Ketene acetal synthesis by /1-elimination of haloacids from halogenated acetals under well controlled conditions using thermal activation (A), ultrasound (US) or micro-wave irradiation [92] (MW) has been described. From a mechanistic point of view, as the TS is more charge delocalized than the GS and the polarity is enhanced during the course of the reaction, a favorable microwave effect can therefore be observed (Eqs. (37) and (38) and Scheme 3.13). 

Cyclizations of enediynes under the action of electrophiles 13KGS129. Cyclization reactions of l,l-bis(trimethylsilyloxy)ketene acetals (synthesis of lactones, cyclic anhydrides, lactone-bridged N-heterocycles, lactone-annulated N-heterocycles) 12SL1283. 

Compounds of special interest whose preparation is described include 1,2,3-benzothiadiazole 1,1-dioxide (a benzyne precursor under exceptionally mild conditions), bis(l,3-diphenylimida-zolidinylidene-2) (whose chemistry is quite remarkable), 6- di-melhylamino)julvene (a useful intermediate for fused-ring non-benzenoid aromatic compounds), dipkenylcyclopropenone (the synthesis of which is a milestone in theoretical organic chemistry), ketene di(2-melhoxyethyl) acetal (the easiest ketene acetal to prepare), 2-methylcyclopenlane-l,3-dione (a useful intermediate in steroid synthesis), and 2-phenyl-5-oxazolone (an important intermediate in amino acid chemistry). 

Schemes 28 and 29 illustrate Curran s synthesis of ( )-hirsutene [( )-1]. Luche reduction58 of 2-methylcyclopentenone (137), followed by acetylation of the resulting allylic alcohol, furnishes allylic acetate 138. Although only one allylic acetate stereoisomer is illustrated in Scheme 28, compound 138 is, of course, produced in racemic form. By way of the powerful Ireland ester enolate Clai-sen rearrangement,59 compound 138 can be transformed to y,S-unsaturated tm-butyldimethylsilyl ester 140 via the silyl ketene acetal intermediate 139. In 140, the silyl ester function and the methyl-substituted ring double bond occupy neighboring regions of space, a circumstance that favors a phenylselenolactonization reac-...

The Ireland-Claisen reaction of ( )-vinylsilanes has been applied to the stereoselective synthesis of syn- and c/nti-2-substituted 3-silyl alkcnoic acids. a R-2-Alkyl-3-silyl acids are prepared by rearrangement of ( )-silyl ketene acetals which are generated in situ from the kinetically formed (Z)-enolate of the corresponding propionate ester40. Chelation directs the stereochemistry of enolization of heteroelement-substituted acetates in such a way that the syn-diastereomers are invariably formed on rearrangement403. 

A few a/j/r -selective amide and imide enolates which arc able to provide high induced diastereo-selectivity have been uncovered very recently. The /V-propionylsultam 1 w hich opens a way to sryn-aldols as described in Section D.1.4.3.2.3.1. also allows the synthesis of r/nh-adducls. For this purpose. 1 is converted into the silyl-iV.O-ketene acetal 2 and subsequently added to aldehydes in a Mukaiyama-type aldol reaction106 to give awi-adducts 310<>f. 

Considerable efforts have been devoted to the stereoselective introduction of a /(-methyl function in intermediates for the synthesis of 1 jS-methylcarbapenems. While the trimethylsilyl trifluoromethanesulfonate catalyzed reaction of a 4-acetoxyazetidinone derivative with ketene acetals shows no selectivity, ketene thioacetals lead to stereoselective formation of the a-methyl isomer108. The zirconium enolate, however, shows high /(-methyl selectivity. 

Because the condensation between a diketene acetal and a diol proceeds without the evolution of volatile byproducts, this method allows the preparation of dense, crossUnked materials by using reagents having a functionality greater than 2 (15). Even though either or both the ketene acetal and alcohol could have functionalities greater than 2, only triols were investigated because the synthesis of trifunctional ketene acetals is extremely difficult. 

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

Mermerian AH, Fu GC (2005) Catalytic enantioselective construction of all-carbon quaternary stereocenters synthesis and mechanistic studies of the C-acylation of silyl ketene acetals. J Am Chem Soc 127 5604—5607... 

A recent synthesis of P-D lactone (Scheme 13.51) used an enantioselective catalytic approach. A conjugate addition of a silyl ketene acetal derived from an unsaturated ester gave an unsaturated lactone intermediate. The catalyst is CuF-(S )-tol-BINAP.30 The catalytic cycle for the reaction is shown below. 

The synthesis of Baccatin HI shown in Scheme 13.57, which was completed by a group led by the Japanese chemist Teruaki Mukaiyama, takes a different approach for the previous syntheses. Much of the stereochemistry was built into the B-ring by a series of acyclic aldol additions in Steps A through D. A silyl ketene acetal derivative... 

Tocopheryl)propionic acid (50) is one of the rare examples that the o-QM 3 is involved in a direct synthesis rather than as a nonintentionally used intermediate or byproduct. ZnCl2-catalyzed, inverse hetero-Diels-Alder reaction between ortho-qui-none methide 3 and an excess of <2-methyl-C,<9-bis-(trimethylsilyl)ketene acetal provided the acid in fair yields (Fig. 6.37).67 The o-QM 3 was prepared in situ by thermal degradation of 5a-bromo-a-tocopherol (46). The primary cyclization product, an ortho-ester derivative, was not isolated, but immediately hydrolyzed to methyl 3-(5-tocopheryl)-2-trimethylsilyl-propionate, subsequently desilylated, and finally hydrolyzed into 50. 

FIGURE 6.37 Synthesis of 3-(5-tocopheryl)-propionic acid (50) by trapping the intermediate ortho-QM 3 with a ketene acetal. Reaction products of 50 are formed in complete analogy to a-tocopherol (1). 

Notably, the Mukaiyama aldol/lactonizahon approach has been used in the total synthesis of panclicin D (2-258) [139b,c] and okinonellin B (2-261) (Scheme 2.61) [139d]. In the synthesis of 2-258, aldehyde 2-254 and the ketene acetal 2-255 were used to prepare the 3-lactone 2-256 with high simple and induced diastereoselectivity. There follows an esterification with the carboxylic acid 2-257. For the synthesis of 2-261, the aldehydes 2-259 and 2-252b were employed as substrates leading initially to the (1-lac tone 2-260. 

A methylenation of cyclic carbonates such as 6/4-132 using dimethyltitanocene to give a ketene acetal, followed by a subsequent Claisen rearrangement, allowed the synthesis of medium-ring lactones such as 6/4-133 in good yields these are otherwise difficult to obtain. In this transformation, 6/4-133 is formed as a l l-mix-ture of the two atropisomers 6/4-133a and 6/4-133b (Scheme 6/4.33). The substrate... 

Clive and coworkers have reported a total synthesis of calicheamicinone, the aglycon of the antitumor agent calicheamicin starting from the Diels-Alder reaction of methyl 3-nitro-propenoate with ketene acetal (Eq. 8.32).54 An asymmetric Diels-Alder reaction between ketene acetal presented in Eq. 8.32 and 3-nitropropenoate derived from (-)-8-phenyl-menthol affords the optically pure adduct, which can be converted into either enantiomer of calicheamicinone (Eq. 8.33).55... 

Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing [4+2] cycloadditions has been described <06JOC3494>. The process involves the in situ generation of 1-aza-1,3-butadiene from a palladium-catalyzed coupling-isomerization reaction of aryl halides (e.g., 18) with propargyl V-tosylamines (e.g., 19). The resulting butadiene then undergoes cycloadditions with V.S -ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17). 

The first synthesis of a cyclopropenone was reported in 1959 by Breslowls who achieved the preparation of diphenyl cyclopropenone (11) by reacting phenyl ketene dimethylacetal with benzal chloride/K-tert.-butoxide. The phenyl chloro carbene primarily generated adds to the electron-rich ketene acetal double bond to form the chlorocyclopropanone ketal 9, which undergoes 0-elimination of HC1 to diphenyl cyclopropenone ketal 10. Final hydrolysis yields 11 as a well-defined compound which is stable up to the melting point (120—121 °C). 

Addition of Ketene Acetals and Enoles In recent years, much attention has been given to the synthesis of optically active nitrogen-containing compounds, with the key step being the highly stereoselective nucleophilic addition of ketene silyl acetals to nitrones (Scheme 2.174). Similar to nitrone cyanations, in ketene silyl acetal reactions one observes an accelerating effect with thiourea derivatives (633). 

The reaction of silyl ketene acetal addition to nitrones has been used for the synthesis of optically active (2S,3S)-benzoyl- and /V- oc-phenyl isoserine (636a) of isoxazolidine nucleoside-analog of thymine polyoxine C(636b) and of... 

The reaction of O-methyl-O-tert-butyldimethylsilyl ketene acetal with N-benzyl- and A-methyl-2,3-O-Mopropylidene D-glyceraldehyde nitrones (292), in the presence of boron trifluoride etherate, affords the corresponding isoxazolidine-5-ones in high yields. These compounds were successfully applied as key intermediates in the synthesis of isoxazolidinyl nucleosides of the L-series (Scheme 2.177) (638). 

Two procedures were developed for C,C-coupling reactions of silyl esters of primary AN. One approach involves two steps and the synthesis of intermediate SENAs according to standard procedures. Another procedure is based on the one-pot reaction of AN with the DBU/TBSOTf system in a ratio of 1 1.1 followed by the addition of silyl ketene acetal and a catalytic amount of TBSOTf. 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Related catalytic enantioseiective processes Representative examples of other catalytic asymmetric Mannich additions are depicted in Scheme 6.31. In 1997, Tomioka demonstrated a Li-catalyzed synthesis of functionalized p-lactams that proceeds through a catalytic enantioseiective Mannich reaction (promoted by 103) [95], and a year later Lectka and his team published a series of reports concerning additions of silyl ketene acetals... 

Cyclic ketene acetals, which have utility as co-polymers with functional groups capable of cross-linking, etc., have been prepared by the elimination of HX from 2-halomethyl-l,3-dioxolanes. Milder conditions are used under phase-transfer conditions, compared with traditional procedures, which require a strong base and high temperatures. Solid liquid elimination reactions frequently use potassium f-butoxide [27], but acceptable yields have been achieved with potassium hydroxide and without loss of any chiral centres. The added dimension of sonication reduces reaction times and improves the yields [28, 29]. Microwave irradiation has also been used in the synthesis of methyleneacetals and dithioacetals [30] and yields are superior to those obtained with sonofication. 

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